Formulation and use thereof

ABSTRACT

Provided are liquid pharmaceutical formulations comprising nicotine in any form for administration essentially to the lungs being acidified and/or alkalized by buffering and/or pH regulation providing for a t max  of nicotine in arterial blood of a subject within a short period of time after administration. The administration is preferably accomplished by spraying an aerosol into the oral cavity for further distribution essentially into the lungs. Methods for manufacturing the formulation is also disclosed, as are uses of the formulation in therapy, such as therapy for treating addiction to tobacco.

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a continuation of and claims priority to U.S.application No. Ser. 10/453,808, filed Jun. 2, 2003 (now allowed), whichis related to and claims priority to U.S. Ser. No. 60/391,886, filedJun. 25, 2002, and Swedish Application Serial Number SE 0201669-9, filedJun. 3, 2002, all of which are explicitly incorporated herein byreference in their entirety.

FIELD

The present invention relates to liquid pharmaceutical formulations fordelivering nicotine to a subject. This invention also relates to methodsand systems for delivering nicotine to a subject as well as themanufacturing and use of said liquid pharmaceutical formulations.

BACKGROUND

Tobacco Dependence and Reduction Thereof

In recent years, with the recognition of the harmful effects of tobaccosmoking, there have been numerous campaigns and programs by governmentalagencies and various health groups and other interested organizations todisseminate information about the adverse health effects resulting fromtobacco smoking. Moreover, and as a result of this recognition of theharmful effects, there have been many programs directed to attempts inreducing smoking incidence.

Nicotine is an organic compound and is the principal alkaloid oftobacco. Nicotine is the chief active ingredient in the tobacco used incigarettes, cigars, snuff and the like. Nicotine is also an addictivedrug, though, and smokers characteristically display a strong tendencyto relapse after having successfully stopped smoking for a time.Nicotine is the world's second most used drug, after caffeine fromcoffee and tea.

The main problem with tobacco smoking is its enormous implications onhealth. Today it is estimated that smoking-related diseases cause some3-4 million deaths per year. In the U.S. Surgeon General's 1988 reporton The Health Consequences of Smoking, it was estimated that in the U.S.alone about 300.000 deaths are caused each year by diseases related tocigarette smoking. In fact, excessive smoking is now recognized as oneof the major health problems throughout the world. This grim consequenceof tobacco smoking has urged many medical associations and healthauthorities to take very strong actions against the use of tobacco.

Even though tobacco smoking is decreasing in many developed countriestoday it is hard to see how the societies could get rid of the world'ssecond most used drug.

The most advantageous thing a heavy smoker can do is to reduce orpreferably even stop smoking completely. Experience shows, however, thatmost smokers find this extremely difficult since, mostly, tobaccosmoking results in a dependence disorder or craving. The WHO has in itsInternational Classification of Disorders a diagnosis called TobaccoDependence. Others, like the American Psychiatric Association call theaddiction Nicotine Dependence. It is generally accepted that thesedifficulties to stop smoking result from the fact that those heavysmokers are dependent on nicotine. The most important risk factors are,however, substances that are formed during the combustion of tobacco,such as carcinogenic tar products, carbon monoxide, aldehydes, andhydrocyanic acid.

Effects of Nicotine

The administration of nicotine can give satisfaction and the usualmethod is by smoking, either by smoking e.g., a cigarette, a cigar or apipe, or by snuffing or chewing tobacco. However, smoking has healthhazards and it is therefore desirable to formulate an alternative mannerof administering nicotine in a pleasurable manner that can be used tofacilitate withdrawal from smoking and/or used as a replacement forsmoking.

Upon smoking of a cigarette, nicotine is quickly absorbed into thesmoker's blood and reaches the brain within around ten seconds afterinhalation. The quick uptake of nicotine gives the consumer a rapidsatisfaction, or kick. The satisfaction, then, lasts during the time ofsmoking the cigarette and for a period of time thereafter. Thepoisonous, toxic, carcinogenic, and addictive nature of smoking hasprovided efforts for methods, compositions and devices, which help inbreaking the habit of smoking.

Nicotine is an addictive poisonous alkaloid C₅H₄NC₄H₇NCH₃, derived fromthe tobacco plant. Nicotine is also used as an insecticide.Approximately forty milligrams of nicotine may kill an adult (MerckIndex).

Nicotine Replacement Products and Prior Art

One way to reduce smoking is to provide nicotine in a form or mannerother than by smoking and some products have been developed to fulfillthis need. Nicotine containing formulations are currently the dominatingtreatments for tobacco dependence.

The success in achieving reduction in the incidence of smoking has beenrelatively poor using presently known products. State of the artinvolves both behavioral approaches and pharmacological approaches. Morethan 80% of the tobacco smokers who initially quit smoking after usingsome behavioral or pharmacological approach to singly reduce smokingincidence generally relapse and return to the habit of smoking at theirformer rate of smoking within about a one year's period of time.

As an aid for those who are willing to stop smoking there are severalways and forms of nicotine replacement products available on the market,such as nicotine chewing gums according to U.S. Pat. No. 3,845,217.Several methods and means have been described for diminishing the desireof a subject to use tobacco, which comprises the step of administeringto the subject nicotine or a derivative thereof as described in e.g.U.S. Pat. No. 5,939,100 (nicotine containing microspheres) and U.S. Pat.No. 4,967,773 (nicotine containing lozenge).

The use of skin patches for transdermal administration of nicotine hasbeen reported (Rose, in Pharmacological Treatment of Tobacco Dependence,(1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skinpatches that are in wide use today can cause local irritation and theabsorption of nicotine is slow and affected by cutaneous blood flow.

Nicotine-containing nose drops have been reported (Russell et al.,British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., BritishJournal of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, aredifficult to administer and are not convenient for use at work or inother public situations. Administration of nicotine by way of deliverydirectly into the nasal cavity by spraying is known from U.S. Pat. No.4,579,858, DE 32 41 437 and U.S. Pat. No. 5,656,255. There may, though,be local nasal irritation with use of nasal nicotine formulations. Thedifficulty in administration also results in unpredictability of thedose of nicotine administered.

Mouth sprays comprising nicotine are known in the art, e.g., accordingto U.S. Pat. No. 6,024,097 wherein is disclosed a method of assisting asmoker in giving up the smoking habit whereby is used a plurality ofaerosol dispensers comprising progressively lesser concentrations ofnicotine. The aerosol is intended to be administered into the mouth. Theliquid in the dispensers essentially consists of nicotine and alcohol.GB 2 030 862 discloses a nicotine-containing aerosol for oraladministration.

A similar mouth spray is disclosed in U.S. Pat. No. 5,810,018, wherebyin addition the aerosol comprises progressively greater concentrationsof at least one selected stimulant.

U.S. Pat. No. 6,413,496 discloses an aerosol device with an active and apropellant. The device may be used for e.g., sublingual administration.Nicotine is mentioned as an active in a long “laundry list” of drugs.There are though no examples on nicotine formulations.

U.S. Pat. No. 5,955,098 discloses a non-polar buccal aerosol spray usinga non-polar solvent. Nicotine is mentioned as one useful active in thisspray.

Inhaling devices resembling a cigarette are known for uptake of nicotinevapors mainly buccally is suggested in U.S. Pat. No. 5,167,242. Aproposal on a nicotine aerosol is disclosed in DE 32 41 437. Newman etal., J Pharma Sci, Vol 85, No 9, September 1996 discloses highlyethanolic systems for administering the asthma medication flunisolide asaerosol to the lungs. Possible utility of these systems for delivery ofnicotine is though not discussed. Buffering of the medication forfacilitating pulmonary delivery is not discussed.

U.S. Pat. No. 4,953,572 and U.S. Pat. No. 4,920,989 disclose one and thesame nicotine-containing aerosol intended for inhalation.

Burch et al. disclose in Am Rev Respir Dis 189; 140:955-957 pulmonaryinhalation of nicotine in conjunction with buccal deposition of anicotine formulation having pH 10.

Andrus et al. disclose in Can Respir J Vol 6 No 6:509-512 a nicotinemicroaerosol inhaler wherein nicotine is present in a non-pH regulatedformulation comprising ethanol and a propellant.

Hitherto is though not known any pharmaceutical formulations or systemsthat efficiently may administer nicotine for uptake mainly in the lungsin order to mimic the nicotine uptake provided by smoking without theadverse effects caused by smoking.

Problems to be Solved

The captioned means and methods do not satisfy the craving that certainusers of tobacco experience. Specifically these means and methodsgenerally do not provide for a sufficiently rapid uptake of nicotinewithout adverse effects. In nicotine replacement therapy, NRT, manysmokers wish to obtain a head rush or very quick onset of nicotinesimilar to the one obtained by inhaling cigarette smoke. None ofhitherto known NRT means may provide for this.

In light of the aforementioned problem there is a strong need andinterest to develop formulations, means and methods for theadministration of nicotine to provide a very fast satisfaction to aperson craving for nicotine or to provide a sense of smokingsatisfaction without smoking, whereby also may be avoided problemsassociated with the prior art means and methods. The present inventionaddresses said need and interest.

SUMMARY OF THE INVENTION

In view of the foregoing disadvantages known in the art when trying todeliver nicotine to a subject so as to obtain a rapid uptake ofnicotine, the present invention provides new and improved products,systems and methods for obtaining a rapid uptake of nicotine essentiallyin the lungs of the subject.

In contrast to smoking, which involves rapid absorption of nicotine, theuse of current nicotine Replacement Therapy (NRT), achieved through useof nicotine formulated in chewing gum, transdermal patch, tablet, nasalspray and inhaler generally provides slower, lower and less variableplasma nicotine concentrations. The arteriovenous differences duringcigarette smoking are substantial, with arterial levels exceeding thevenous levels six- to ten-fold. The instant relief from craving duringcigarette smoking is believed to be achieved by the “nicotine buzz”, thesharp rise of nicotine concentration in arterial blood, the arterialblood being transported from the lung alveoli via the heart to the brainwithin seconds. The nicotine level in the brain declines betweencigarettes as the nicotine is distributed to other body tissues. Thisdecline in nicotine level provides an opportunity for resensitization ofthe nicotine receptors in the brain, allowing some positivereinforcement despite the development of acute tolerance. The currentNRT options do not provide this initial sharp rise in arterial bloodlevel. Even if the success rates for smoking cessation with current NRTare twice those obtained using placebo, such therapy is still not verysuccessful. Only up to 30 percent of all people succeed in theirattempts to quit smoking. Therefore, there is a strong need for a moreefficient therapy for smoking cessation. This invention providescigarette-like delivery of nicotine.

Objects of the present invention are to provide an efficient andeffective product, as well as methods and systems for an essentiallypulmonary uptake of nicotine in a subject to avoid the disadvantages ofpreviously known products and methods.

Thus, the present invention provides a method for delivering nicotine inany form to a subject comprising administering to a subject a liquidpharmaceutical formulation containing nicotine in any form essentiallyinto the lungs of the subject and allowing the nicotine in any form tobe absorbed into the systemic circulation of the subject essentially bypulmonary uptake of nicotine as well as a method for manufacturing saidliquid pharmaceutical formulation.

The present invention also provides a method for obtaining reduction ofthe urge to smoke or use tobacco containing material and/or forproviding a fast sense of smoking satisfaction without smoking,comprising the steps of replacing at least part of the tobaccocontaining material, e.g., between 20 and 100% of the tobacco containingmaterial, with said liquid pharmaceutical formulation, administering toa subject a liquid pharmaceutical formulation containing nicotine in anyform essentially to the lungs of the subject and allowing the nicotineto be systemically absorbed by the subject essentially by pulmonaryuptake of nicotine.

Furthermore, the present invention provides a system for deliveringnicotine in any form to a subject, comprising said liquid pharmaceuticalformulation and at least one other means for obtaining reduction of theurge to smoke or use of tobacco as well as a system for obtainingreduction of the urge to smoke or otherwise use of tobacco and/or forproviding a sense of smoking satisfaction without smoking, comprising aliquid pharmaceutical formulation as per above and at least one othermethod for obtaining reduction of the urge to smoke or otherwise usetobacco. Said system may be a system wherein the at least one othermethod is selected from the group consisting of administration throughchewing gums, nasal sprays, mouth sprays, gargles, transdermal patches,lozenges, tablets and parenteral methods, subcutaneous methods,intravenous methods, rectal methods, vaginal methods and transmucosalmethods; or other uses of tobacco.

The present invention provides for a flexible, convenient and discreteuse in comparison with other means for transmucosal delivery ofnicotine, e.g., chewing gums, lozenges, tablets, mouth sprays and otherdevices attempting to provide nicotine inhalation. No chewing or suckingis necessary. Further, the present liquid pharmaceutical formulationprovides nicotine in a form being directly absorbable by a subject. Thenicotine in chewing gums, lozenges and tablets need pass atransformation phase, involving e.g., mastication, disintegration,melting and/or dissolution, prior to being present in a directlyabsorbable form. A nicotine patch provides for a discreteadministration, but does not provide for a fast uptake of nicotine.Also, the present invention directly mimics the way a smoker receivesnicotine and provides for a head rush and very quick onset of nicotineessentially being the same as experienced with smoking. Therefore asmoker very easily may adapt to using the present invention.

Preferred embodiments of a product according to the present invention isbuffered and/or pH regulated in such a way that the pH of the liquidpharmaceutical formulation is from around pH 3 to around pH 7,preferably from around pH 4 to around pH 6.

Use of said product will according to the invention rapidly delivernicotine in any form to a subject and will also provide for obtaining aquick and/or sustained and/or complete reduction of the urge to smoke oruse tobacco and/or for providing a sense of smoking satisfaction withoutsmoking resembling the sense of smoking satisfaction obtained afterregular smoking or use of tobacco.

Preferably the present liquid formulation is an ethanol-basedformulation or an aqueous-based formulation. Principally theserespective formulations are manufactured as follows:

Ethanol-Based Formulation:

-   -   Take the required amount of ethanol.    -   Add the required amount of water.    -   Add the required amount of propylene glycol and/or glycerol.    -   Add the required amount of organic and/or inorganic acid.    -   Mix the ingredients until homogeneous.    -   Add the required amount of nicotine or nicotine in salt form.    -   Optionally add further ingredients    -   Mix the ingredients until homogeneous.    -   Adjust apparent pH, targeting 3.0 to 5.5.    -   All operations may be done at room temperature and no other        ingredients, such as preservatives, are required.

Aqueous-Based Formulation:

-   -   Take the required amount of water.    -   Add the required amount of salt, e.g., sodium chloride.    -   Add the required amount of organic and/or inorganic acid.    -   Mix the ingredients until homogeneous.    -   Add the required amount of preservative, such as benzalkonium        chloride.    -   Add the required amount of nicotine or nicotine in salt form.    -   Optionally add further ingredients    -   Mix the ingredients until homogeneous.    -   Adjust pH, targeting 5.5 to 7.0.

All operations may be done a room temperature.

The buffering agent and the pH regulating means

In a preferred embodiment of the present invention, the composition ofthe liquid has its pH adjusted to between 3 and 7. Thereby the pH isclose to the physiological pH without causing significant irritation. Asthe pKa for the acid dissociation constant of the mono protonated formof nicotine in an aqueous system is approximately 8.0 at 20° C., at pH'sin the range 5 to 7 virtually all of the nicotine (90% to 99.9%) existsin its mono protonated form and is thereby prevented from existing inthe vapor phase. For the ethanol-based system the apparent pKa isapproximately 6.5 at 20° C. and, consequently, at apparent pHs in therange 3 to 5.5 virtually all of the nicotine (90% to 99%) exists in itsmono-protonated form and is thereby prevented from existing in the vaporphase.

Hence and according to the invention, the liquid pharmaceuticalformulation is acidified and/or alkalized by buffering and/or pHregulation. This may be achieved by including physiologically acceptablebuffering substances or agents, or by other means. With other means itis intended to include buffering by any component in the product, whichmay not normally act as a buffering agent, such as a self-bufferingadditive and/or pH regulating forms of nicotine. Accordingly, for use inthe present invention, the terms “buffering agent” and “pH regulatingagent” may include any agent capable of regulating pH.

In some embodiments of the present invention, buffering and/or pHregulation decreases the pH of the pharmaceutical formulations of thepresent invention thereby causing uptake of nicotine to take placemainly in the lungs rather than in the oral cavity or in the respiratorytract. Hence, only small amounts of nicotine are swallowed and reach thegastrointestinal (GI) tract. Nicotine that reaches the GI tract will besubjected to first pass metabolism, which reduces the total amount ofintact nicotine absorbed. This means that the bioavailability ofnicotine that is not co-administered with a buffer according to theinvention will generally be lower than when administered together with abuffer.

A titration curve for nicotine with sulphuric acid in a 90:10ethanol:water matrix shows that the apparent pKa of nicotine in 90%ethanol is 6.5. This means that at apparent pH 6.5, 50% of the nicotineis in its free base form. Separately, an Andersen Cascade Impactor (ACI)experiment, performed with a formulation at an apparent pH=4.0,demonstrated that nicotine (in its salt form at this apparent pH)remains in the liquid droplets. The majority of the droplets has sizesless than 3.3 microns and would be deposited in the lungs uponinhalation. By comparison, an ACI experiment, performed with aformulation at an apparent pH=6.0, demonstrated that part of thenicotine (approximately 15% of it is in its free base form at thisapparent pH) escapes from the liquid droplets as a vapor. It is wellknown that inhaled nicotine vapor deposits in the oral cavity.Therefore, the nicotine in its base form, inhaled in this formulationwould not be deposited in the lungs.

In conclusion, the above set of experiments demonstrates the utility ofthe present invention for delivering nicotine to the lungs.

An acidifying effect may be achieved by the use of one or more bufferingagents selected from the group consisting of citric acid, phosphoricacid, acetic acid, hydrochloric acid, nitric acid, sulphuric acid andacidic salts thereof.

An alkalizing effect may be achieved by the use of one or more bufferingagents selected from the group consisting of a carbonate, such asmono-carbonate, bicarbonate or sesquicarbonate; glycinate, phosphate,glycerophosphate, acetate, gluconate or citrate of an alkali metal, suchas potassium or sodium, or of ammonium, and mixtures thereof; and/or bythe use of pH regulating agents, such as agents selected from the groupconsisting of sodium hydroxide, potassium hydroxide, calcium hydroxideand calcium oxide; and/or by using at least partly pH regulating formsof nicotine.

The pH regulation may also be obtained by using pH-regulating forms ofnicotine, e.g., nicotine free base.

The nicotine may be administered in different forms, e.g., in differentcomplexes or salts or as free base.

DETAILED DESCRIPTION

The terms “tobacco”, “tobacco containing material” and similar areherein intended to mean such material for any type of use of tobaccoincluding smoking, snuffing or chewing whereby is used inter alia acigarette, a cigar, pipe tobacco, snuff and chewing tobacco.

The term “fast reduction of the urge to smoke or use tobacco ” is hereinintended to mean an initial priming of the subject so as to achieve areduction of the urge to smoke or use tobacco.

The term “buccal” and “buccally” are herein intended to pertain to allof or any part of the soft tissue lining of the oral cavity.

The term “pulmonary uptake” is herein intended to mean that the activeagent passes the lung tissue whereupon it enters the systemiccirculation.

The term “delivery to the lungs” or “administration to the lungs” andsimilar is herein intended to mean deposition of an active agent on lungtissue.

The term “incidence of administration” is herein intended to meanadministration of one or more single doses of the liquid pharmaceuticalformulation within the same time frame, said time frame being dependenton the needs of the subject receiving the administration, said timeframe extending from a few seconds to around ten minutes.

The Active Ingredient

According to the invention, the liquid pharmaceutical formulationproduct comprises nicotine in any form to provide an essentiallypulmonary uptake of the nicotine so as to obtain a rapid “nicotine kickor buzz” or “nicotine head rush” or reduction of the urge to smokeand/or use tobacco. Thereby may also be achieved a systemic maintenancelevel of nicotine.

The nicotine should be in a form facilitating the uptake of the nicotinein the lungs.

The nicotine may act as a stimulant to e.g., obtain a rapid reduction ofthe urge to smoke or to use tobacco.

With nicotine it is intended to include nicotine,3-(1-methyl-2-pyrrolidinyl)-pyridine, including the racemate and theenantiomers, with its base form, including synthetic nicotine as well asnicotine extracts from tobacco plants, or parts thereof, such as thegenus Nicotiana alone or in combination; or pharmaceutically acceptablesalts.

In preferred embodiments, the nicotine in any form is selected from thegroup consisting of the free base form of nicotine or a nicotine salt.

Preferred nicotine salts are salts with the following acids Formic,Acetic, Propionic, Butyric, 2-Methylbutyric, 3-Methylbutyric, Valerie,Lauric, Palmitic, Tartaric, Citric, Malic, Oxalic, Benzoic, Gentisic,Gallic, Phenylacetic, Salicylic, Phthalic, Picric, Sulfosalicylic,Tannic, Pectic, Alginic, Hydrochloric, Chloroplatinic, Silicotungstic,Pyruvic, Glutamic and/or Aspartic.

Most preferred nicotine salts are tartrate, hydrogen tartrate, citrateand malate.

The most preferable embodiment incorporates nicotine as the free baseform or as a water-soluble pharmaceutically acceptable salt.

According to the invention, the uptake of the nicotine in the lungs isimproved in relation to the lung uptake obtained by pulmonaryadministration of a theoretical liquid pharmaceutical formulation devoidof buffering agents or devoid of pH-regulating means.

Amount of the Nicotine in the Liquid Pharmaceutical Formulation

The nicotine in any form is according to the invention formulated toprovide the subject with a dose to achieve an effect. The effect may beto provide a sense of smoking satisfaction without smoking. Anothereffect of the administered nicotine in any form may be a reduction ofthe urge to smoke or use tobacco.

The effect may also be a combination of a reduction of said urge andproviding a sense of smoking satisfaction without smoking. The amount ofthe nicotine should be sufficient to provide such an effect in asubject. This amount may, of course, vary from person to person.

According to the invention, embodiments of the liquid pharmaceuticalformulation comprise nicotine in such concentrations that the amount ofnicotine delivered at each incidence of administration is about 0.05-10mg calculated as the free base form of nicotine, preferably about 0.5-5mg and most preferably about 0.5-1 mg.

Release and Uptake of Nicotine

The time point for reaching a sense of satisfaction or reduction of urgeto smoke or use tobacco after administration is individual, but may inexisting pharmaceutical forms for administering nicotine generally bereached after approximately 30 minutes when regarded as coinciding witht_(max). According to the present invention, such a sense ofsatisfaction may be reached after a shorter period of time due to arapid transmucosal uptake in the lungs due to the buffering and/or pHregulation and due to the absence of rate-limiting steps, such as tabletor lozenge melting, tablet or lozenge disintegration and dissolution andchewing gum mastication, followed by drug dissolution.

As used herein, “t_(max)” is the time to reach maximum concentration ofnicotine in the blood of a subject following administration of a singledosage of nicotine to the subject.

The Liquid Phase

The liquid phase of the present liquid pharmaceutical formulation maycomprise water. The liquid phase may also comprise an alcohol, such asethanol, glycerol, propylene glycol and polyethylene glycol, or mixturesthereof. Further it may comprise mixtures of the above ingredients.

One or more of the compounds of the liquid pharmaceutical formulationmay be solubilized in one or more surface active agents and/oremulsifiers, such as nonionic, cationic, anionic or zwitterionicsurfactants, including amphiphilic block copolymers, or mixturesthereof.

Other Additives to the Liquid Pharmaceutical Formulation

Other additives may be added optionally to the liquid pharmaceuticalformulation. These include tonicity agents, preferably chosen fromsugars and inorganic salts.

Method for Delivering Nicotine in Any Form to a Subject

According To The Invention, a method for delivering nicotine in any formto a subject comprises the steps of:

-   -   a) administering to a subject a liquid pharmaceutical        formulation product containing nicotine in any form according to        the invention for delivery into the lungs of the subject, and    -   b) allowing the nicotine in any form in the liquid        pharmaceutical formulation to be absorbed into the blood plasma        of the subject essentially by pulmonary uptake.

One embodiment results in a t_(max) of nicotine in arterial blood of thesubject in less than about 10 minutes.

A further embodiment results in a t_(max) of nicotine in arterial bloodof the subject in less than 3 minutes and less than 1 minute.

In still one further embodiment, said nicotine in any form is absorbedresulting in a t_(max) of nicotine in venous blood of the subject inless than 20 minutes, preferably in less than 15 minutes.

Method for Obtaining Reduction of the Urge to Smoke or to Use Tobacco

A method for obtaining reduction of the urge to smoke or usetobacco-containing material and/or for providing a sense of smokingsatisfaction without smoking according to the invention comprises thesteps of:

a) replacing at least partly the tobacco containing material with aliquid pharmaceutical formulation according to the present invention,

b) administering to a subject a liquid pharmaceutical formulationcontaining nicotine in any form according to the present invention fordelivery essentially to the lungs of the subject, and

c) allowing the nicotine in any form in the liquid pharmaceuticalformulation to be absorbed by the subject essentially by pulmonaryuptake.

The Administration to the Lungs Preferably Takes Place byAerosolization.

Aerosolization is preferably achieved by use of a nebulizer. Forconventional nebulizers, the nicotine is dissolved in a solution, seeabove, and the drug solution is placed in the nebulizer cup. A highvelocity air stream is passed over a capillary tube extending into thedrug solution. The low pressure created by this jet stream draws theliquid into the jet stream. Internal baffling creates a standing aerosolcloud from which the subject receives the dose upon inhalation. Theremainder of the aerosol is recycled within the nebulizer.

Recently, portable nebulizers, oftentimes referred to as Air MistInhalers or AMIs, have emerged. These devices generate the standingaerosol cloud by various techniques such as ultrasonic methods,mechanical break-up and electrohydrodynamics. These AMIs overcome mostof the drawbacks of conventional nebulizers (bulky size, need for anexternal power source, low efficiency, long treatment times, etc.). Onesuch AMI is disclosed in Am Rev Respir Dis 1989; 140: 955-957. Moreefficient AMIs are envisageable.

In one embodiment said nicotine in any form reaches a t_(max) ofnicotine in arterial blood of the subject in less than 10 minutesirrespective of the dose of nicotine.

In further embodiments said nicotine in any form reaches a t_(max) ofnicotine in arterial blood of the subject in less than 3 minutes or lessthan 1 minute irrespective of the dose of nicotine.

In still one further embodiment said nicotine in any form reaches at_(max) of nicotine in venous blood of the subject in less than 20minutes, preferably in less than 15 minutes, irrespective of the dose ofnicotine.

Even further embodiments of the method for delivering nicotine to asubject may comprise the steps of combining at least one other methodfor obtaining reduction of the urge to smoke or use of tobacco.

The liquid pharmaceutical formulation may be used for obtaining a quickand/or sustained and/or complete reduction of the urge to smoke or usetobacco and/or for providing a sense of smoking satisfaction withoutsmoking as further discussed below.

The fast relief provides the subject with a sense of rapid smokingsatisfaction without smoking.

One embodiment reduces the urge to smoke or use of tobacco by reaching at_(max) of nicotine in arterial blood of the subject in less than 10minutes by the use of a liquid pharmaceutical formulation according tothe invention.

Further embodiments reduce the urge to smoke or use tobacco by reachinga t_(max) of nicotine in arterial blood of the subject in less than 3minutes or less than 1 minute by the use of a liquid pharmaceuticalformulation according to the invention.

Still one further embodiment reduces the urge to smoke or use tobacco byreaching a t_(max) of nicotine in venous blood of the subject in lessthan 20 minutes, preferably in less than 15 minutes by the use of aliquid pharmaceutical formulation according to the invention.

Cessation of the Urge to Smoke or Use Tobacco

For some of the users, it may be a goal to terminate the usage ofnicotine completely, due to several reasons e.g., health, economical,social or behavioral. This may be achieved by further decreasing thedelivered amount of nicotine in any form gradually over time. Inspecific embodiments of the invention, the method described above forobtaining craving relief may further comprise the steps of decreasingthe amount of nicotine in the liquid pharmaceutical formulationgradually over time, and/or the steps of reducing the incidence ofadministration of the liquid pharmaceutical formulation gradually overtime, and/or the steps of reducing the dosage size of the liquidpharmaceutical formulation gradually over time, so as to achieve arelief of tobacco craving and/or to achieve a sense of smokingsatisfaction. This method results in a weaning process gradually overtime.

Different types of smokers reach the sense of reduced craving atdifferent plasma levels of nicotine. This may, of course, affect theindividual types of programs for administering a liquid pharmaceuticalformulation according to the invention. Different types of smokersinclude e.g., peak seekers or smokers that crave for a plasma level ofnicotine constantly being above the level below which withdrawalsymptoms occur.

One strategy may be to lower the frequency of administering the liquidpharmaceutical formulation. Other embodiments include varying the doseof the nicotine in said liquid pharmaceutical formulation as well as thecombination of these two embodiments.

Systems for Delivering Nicotine and for Obtaining Craving Relief

According to the invention there is a system for delivering nicotine inany form to a subject. Such a system comprises a liquid pharmaceuticalformulation according to the invention and at least one other means forobtaining reduction of the urge to smoke.

Another system according to the invention may be a system for obtainingreduction of the urge to smoke or use tobacco and/or for providing asense of smoking satisfaction without smoking. Such a system comprises aliquid pharmaceutical formulation according to the invention and atleast one other method for obtaining reduction of the urge to smoke oruse tobacco. Other methods may be a concomitant or concurrent methodselected from the group consisting of administration through chewinggums, nasal sprays, transdermal patches, mouth sprays, lozenges, tabletsand parenteral methods, subcutaneous methods, intravenous methods,rectal methods, vaginal methods and transmucosal methods; or use oftobacco.

In a specific embodiment, the at least one other method comprisesadministration of nicotine.

Use of the Liquid Pharmaceutical Formulation

The use of the liquid pharmaceutical formulation according to theinvention is for obtaining a fast and/or sustained and/or completereduction of the urge to smoke and use tobacco or for providing a senseof smoking without smoking as described above.

The dose of the nicotine is chosen to give the subject an individualsensory perception and satisfaction with an effect of the nicotine inany form. The use of the liquid pharmaceutical formulation may also be asole use according to the invention or a combination with other means ormethods known in the field of drug abuse. Specifically, the presentinvention may be used in combination with other means as described abovein the methods in the paragraphs above.

The use may give a quick reduction of the urge to smoke or use tobaccowhereby is reached a t_(max) of nicotine in arterial blood in less thanabout 10 minutes.

In other embodiments, the use of the liquid pharmaceutical formulationaccording to the invention will reduce the urge to smoke or use tobaccoby reaching a t_(max) of nicotine in arterial blood of the subject inless than about 3 minutes or in less than about 1 minute.

In a further embodiment, the use of the liquid pharmaceuticalformulation according to the invention will reduce the urge to smoke oruse tobacco by reaching a t_(max) of nicotine in venous blood of thesubject in less than about 20 minutes, preferably in less than about 15minutes.

According to the invention, a use of a liquid pharmaceutical formulationaccording to the invention is for delivering nicotine in any form to asubject.

In different embodiments, the delivering of nicotine in any form resultsin a t_(max) of nicotine in arterial blood of the subject in less thanabout 10 minutes, in less than about 3 minutes and/or in less than about1 minute, and/or results in a t_(max) of nicotine in venous blood of thesubject in less than about 20 minutes, preferably in less than about 15minutes.

Use for Therapy, Treatment and Manufacturing

The liquid pharmaceutical formulation product according to the inventionmay be used in therapy. Said therapy may be a treatment of a disease ormedical indication selected from the group consisting of reduction inuse of tobacco, cessation of use of tobacco, other use of tobacco,temporary abstinence from abstaining from use of tobacco, Alzheimer'sdisease, Crohn's disease, Parkinson's disease, Tourette's syndrome, andulcerative colitis; and weight control.

Nicotine in any form may be used for the manufacturing of a liquidpharmaceutical formulation according to the invention for the treatmentof a disease or medical indication selected from the group consisting ofreduction in use of tobacco, cessation of use of tobacco, other use oftobacco, temporary abstinence from abstaining from using tobacco,Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette'ssyndrome, and ulcerative colitis; and weight control.

A liquid pharmaceutical formulation comprising nicotine in any form foradministration essentially to the lungs being acidified and/or alkalizedby buffering and/or pH regulation providing for a t_(max) of nicotine inarterial blood of a subject within a short period of time afteradministration.

The administration is preferably by spraying an aerosol into the oralcavity for further distribution essentially into the lungs. A method formanufacturing said formulation. Use of said formulation in therapy, suchas therapy for treating addiction to tobacco.

All publications and patent documents cited above are herebyincorporated by reference in their entirety for all purposes to the sameextent as if each were so individually denoted.

EXAMPLES

The below examples are non-limiting and for illustrating the presentinvention. Alternatives and variations of the below examples within thescope of the present invention as per the below claims may be carriedout by a person skilled in the art. Ingredients as per the belowexamples may be exchanged for equivalent ingredients, preferably as perabove.

As stated under the captioned Summary of the invention the presentliquid pharmaceutical formulation is preferably an ethanol- or anaqueous-based formulation in principle being manufactured as follows:

Ethanol-Based Formulation:

-   -   Take the required amount of ethanol.    -   Add the required amount of water.    -   Add the required amount of propylene glycol and/or glycerol.    -   Add the required amount of organic acid and/or inorganic acid.    -   Mix the ingredients until homogeneous.    -   Add the required amount of nicotine as free base or nicotine in        salt form.    -   Optionally add further ingredients.    -   Mix the ingredients until homogeneous.    -   Adjust apparent pH, targeting 3.0 to 5.5.    -   All operations may be done at room temperature and no other        ingredients, such as preservatives, are required.

Aqueous-Based Formulation:

-   -   Take the required amount of water.    -   Add the required amount of salt, e.g., sodium chloride.    -   Add the required amount of organic and/or inorganic acid.    -   Mix the ingredients until homogeneous.    -   Add the required amount of preservative, such as benzalkonium        chloride.    -   Add the required amount of nicotine as free base or nicotine in        salt form.    -   Optionally add further ingredients.    -   Mix the ingredients until homogeneous.    -   Adjust pH, targeting 5.5 to 7.0.

All operations may be done at room temperature.

The present liquid pharmaceutical formulation is not limited to theabove embodiments or to the below Examples.

Example 1

Manufacturing of 100 ml ethanol-based formulation with 10 μg nicotine/μland pH around 3.0.

60 g 99% ethanol and 9.9 g (polyethylene) propylene glycol wasthoroughly mixed with 1000 mg nicotine at room temperature. ThereafterpH was adjusted to 3.0 using diluted sulphuric acid. Thereafter thevolume was adjusted to 100.0 ml with addition of 99% ethanol. Thesolution was aseptically filtered and put into appropriate sterilecontainer.

Example 2

Manufacturing of 100 ml ethanol-based formulation with 10 μg nicotine/μland pH around 4.0.

60 g 99% ethanol and 9.9 g (polyethylene) propylene glycol wasthoroughly mixed with 1000 mg nicotine at room temperature. ThereafterpH was adjusted to 4.0 using diluted HCl. Thereafter the volume wasadjusted to 100.0 ml with addition of 99% ethanol. The solution wasaseptically filtered and put into appropriate sterile container.

Example 3

Manufacturing of 100 ml ethanol-based formulation with 50 μg nicotine/μland pH around 5.0.

60 g 99% ethanol and 9.9 g (polyethylene) propylene glycol wasthoroughly mixed with 5000 mg nicotine at room temperature. ThereafterpH was adjusted to 5.0 using diluted sulphuric acid. Thereafter thevolume was adjusted to 100.0 ml with addition of 99% ethanol. Thesolution was aseptically filtered and put into appropriate sterilecontainer.

Example 4

Manufacturing of 100 ml ethanol-based formulation with 50 μg nicotine/μland pH around 5.5.

60 g 99% ethanol and 9.9 g glycerol was thoroughly mixed with 5000 mgnicotine at room temperature. Thereafter pH was adjusted to 5.5 usingdiluted sulphuric acid. Thereafter the volume was adjusted to 100.0 mlwith addition of 99% ethanol. The solution was aseptically filtered andput into appropriate sterile container.

Example 5

Manufacturing of 100 ml aqueous-based formulation with 10 μg nicotine/μland pH around 5.0.

60 g distilled water, 0.9 g sodium chloride and 100 mg citric acid wasthoroughly mixed with 1000 mg nicotine at room temperature. ThereafterpH was adjusted to 5.0 using 0.1% citric acid. Thereafter the volume wasadjusted to 100.0 ml with addition of distilled water. The solution wasaseptically filtered and put into appropriate sterile container.

Example 6

Manufacturing of 100 ml aqueous-based formulation with 10 μg nicotine/μland pH around 7.0.

60 g distilled water and 0.9 g sodium chloride was thoroughly mixed with1000 mg nicotine at room temperature. Thereafter pH was adjusted to 7.0using 0.1% citric acid. Thereafter the volume was adjusted to 100.0 mlwith addition of distilled water. The solution was aseptically filteredand put into appropriate sterile container.

Example 7

Manufacturing of 100 ml aqueous-based formulation with 50 μg nicotine/μland pH around 5.0.

60 g distilled water, 0.9 g sodium chloride and 100 mg citric acid wasthoroughly mixed with 5000 mg nicotine at room temperature. ThereafterpH was adjusted to 5.0 using diluted HCl. Thereafter the volume wasadjusted to 100.0 ml with addition of distilled water. The solution wasaseptically filtered and put into appropriate sterile container.

Example 8

Manufacturing of 100 ml aqueous-based formulation with 50 μg nicotine/μland pH around 6.0.

60 g water, 0.9 g sodium chloride and 100 mg citric acid was thoroughlymixed with 5000 mg nicotine at room temperature. Thereafter pH wasadjusted to 6.0 with diluted HCl Thereafter the volume was adjusted to100.0 ml with addition of distilled water. The solution was asepticallyfiltered and put into appropriate sterile container.

Example 9

Manufacturing of 100 ml aqueous-based formulation with 10 μg nicotine/μland pH around 5.0.

60 g distilled water, 0.9 g sodium chloride and 100 mg citric acid wasthoroughly mixed with 3072 mg nicotine hydrogen tartrate at roomtemperature. Thereafter pH was adjusted to 5.0 using diluted HCl.Thereafter the volume was adjusted to 100.0 ml with addition ofdistilled water. The solution was aseptically filtered and put intoappropriate sterile container.

Example 10

Manufacturing of 100 ml aqueous-based formulation with 50 μg nicotine/μland pH around 6.0.

60 g water, 0.9 g sodium chloride and 100 mg citric acid was thoroughlymixed with 15.362 g nicotine hydrogen tartrate at room temperature.Thereafter pH was adjusted to 6.0 using diluted HCl. Thereafter thevolume was adjusted to 100.0 ml with addition of distilled water. Thesolution was aseptically filtered and put into appropriate sterilecontainer.

The liquid pharmaceutical formulation may within the inventive conceptcomprise ingredients in other amounts than in the above examples.

Hence the liquid pharmaceutical formulation may be essentiallyalcohol-based, whereby it comprises nicotine in any form, at least 50%,preferably at least 90% and most preferably around 99% alcohol,preferably ethanol, one or more buffering agents, and optionallypropylene glycol, one or more organic or inorganic acids, and otheradditives.

Also the liquid pharmaceutical formulation may be essentiallywater-based, whereby it comprises nicotine in any form, at least 50%,preferably at least 90% and most preferably at least 99% water, one ormore buffering agents, and optionally one or more preservatives andother additives.

Further, also other percentage ranges are within the inventive concept.

What is claimed:
 1. A pharmaceutical aerosol formulated foradministration to a subject's lungs comprising liquid droplets, saidliquid droplets comprising un-complexed nicotine, alcohol, and abuffering or pH regulating agent in an amount sufficient to adjust thepH of the formulation to an apparent pH in the range of 3 to 5.5.
 2. Thepharmaceutical aerosol of claim 1 comprising a buffering agent, whereinsaid buffering agent is citric acid, phosphoric acid, acetic acid,hydrochloric acid, nitric acid, sulphuric acid, or acidic salts thereof;or, wherein said buffering agent is a carbonate, a glycinate, aphosphate, a glycerophosphate, an acetate, a gluconate, or a citrate. 3.The pharmaceutical aerosol of claim 1 comprising a pH regulating agent,wherein said pH regulating agent is sodium hydroxide, potassiumhydroxide, calcium hydroxide, calcium oxide, or pH regulating forms ofnicotine.
 4. The pharmaceutical aerosol of claim 1, wherein said liquiddroplets have an acidic pH and said buffering or pH regulating agent iscitric acid, phosphoric acid, acetic acid, hydrochloric acid, nitricacid, sulphuric acid, acidic salts thereof, or partly pH regulatingforms of nicotine.
 5. The pharmaceutical aerosol of claim 1, whereinsaid nicotine is present as a free base, a nicotine salt, a nicotinemetabolite, or any combination thereof.
 6. The pharmaceutical aerosol ofclaim 1, wherein the amount of nicotine administered to the lungs isabout 0.05-10 mg calculated as the free base form of nicotine.
 7. Thepharmaceutical aerosol of claim 1, wherein said liquid droplets furthercomprise water.
 8. The pharmaceutical aerosol of claim 1 wherein saidliquid droplets further comprise alcohol.
 9. The pharmaceutical aerosolof claim 1, wherein said formulation comprises water and an alcohol. 10.The pharmaceutical aerosol of claim 1, further comprising a surfaceactive agent or an emulsifier.
 11. The pharmaceutical aerosol of claim1, wherein said liquid droplets further comprise water, sodium chloride,and ethanol.
 12. The pharmaceutical aerosol of claim 1, wherein saidformulation further comprises one or more tonicity agents.
 13. Thepharmaceutical aerosol of claim 1, wherein said liquid droplets compriseat least 90% alcohol by weight.
 14. The pharmaceutical aerosol of claim1 wherein said liquid droplets further comprise propylene glycol andethanol.
 15. The pharmaceutical aerosol of claim 1, wherein said liquiddroplets further comprise water and alcohol, and wherein said alcohol isa mixture of ethanol and at least one of propylene glycol or glycerol;and wherein said buffering agent or pH regulating agent is an acid.